Process of nitrating furan derivatives



Patented Nov. 29, less sauce PRUCESS @F NITRATING FURAN DERIVATIVES i tialter nei, l-iighiand Park, N. 5., and John H.

Coleman and William B. Stillman, Norwich,

assignors to Eaton Laboratories, lino,

Norwich, N. EL, a corporation or New York No Drawing.

Application August is, 1946,

Serial No. 691,174

. j 1''? Claims. (Cl. 260-345) This invention relates to nitrofurans and aims t provide improvements in the process of nitrating furan derivatives.

- The nitration of a furan derivative involves the preparation of a nitration intermediate and the conversion of that intermediate into the nitrofuran. In the past, this has been accomplished on a laboratory scale through a three-step process (see Gilman and Wright, J. A. C. S. 52: 2550, 4165 (1930) In the first step, the nitration intermcdiate was prepared; in the second step, the nitration intermediate was separated out of the nitration solution; and in the third step, the nitration intermediate was converted into the nitrofuran.

The first step involved the use of fuming nitric acid at a temperature of -5 C. or less. Fuming nitric acid (sp. gr. 1.50) was added to acetic anhydride at a temperature of 5 C. to lii C. to provide a nitrating mixture. A solution of the furan derivative in acetic anhydride was then added to the nitrating mixture, seeping the temperature of the reaction between 5 C. and -l0 C. After the addition had been completed, the solution was stirred for about three hours at 5 C. This resulted in the production of an unstable, oily intermediate of unknown composition.

In the second step, the nitration intermediate was separated from the balance of the nitration solution by pouring the solution on a large volume of ice and neutralizing the mixture with sodium hydroxide. An aqueous layer was formed and this was decanted, leaving the nitration intermediate together with impurities.

The third step, conversion of the nitration intermediate into the nitroiuran, was accomplished by to the material left after decantation of the a ,Iueous layer in step two, a large volume of pyridine, keeping the temperature below 40 C, by the addition of ice. After completion of the reaction, the mixture was diluted with two to three volumes of water. The nitroiuran so obtained was or her filtered out by suction or extracted with ether, wa hed free of pyridine with dilute acetic acid, washed with cold water to free the nitroiuran of excess acetic acid, dried, and

finally rec ystal-'sc from alcohol or distilled.

The old three step process is not adapted to large-scale n tration of furan derivatives. It is dangerous, or zbersorne, slow and expensive, and results in a very low yield, and in a procuct which contains high percentage of impurities.

We have discovered that a nitration intermediate can be formed through the of concentrated nitric rather than ruining nitric We have discovered also that a nitration intermediate can be converted directly into the nitrofuran by adding water and a base to produce a pI-I value within the range of about 1.79 to about one mole of furan derivative.

4.66. The concentrated nitric acid can be used at temperatures which are much higher than the temperatures permissible when fuming nitric acid is used; the conversion can be effected through the use of any base which produces a buiier system in the presence of acetic acid; and the step of separating the unstable nitration intermediate out of the nitration solution is un necessary.

Our invention makes possible the nitration of furan derivatives on a large scale in safety. It is much more speedy and reliable than the old three-step process, can be carried out with much less equipment and gives a higher yield and a purer roduct.

A nitrated iuran derivative is produced in ac cordance with our invention in two steps, The first step consists in the formation of a n? ration intermediate by slowly adding the furan derivative to acetic anhydride concentrated nitric acid. The temperature at which the addition is made is within the range of (3 C. to 5 3 C. and the mixture is maintained at about that temperature until the reaction is complete. The second step consists in converting the nitration intermediate into the nitrated furan derivative. This is accomplished by diluting the nitration mixture with water and adding to it a base which forms a buffer system in the presence of acetic acid. Sufficient of the base is added to produce a pH value within the range of about 1.79 to about 4.66. The temperature of the mixture during this addition is kept within the range of 25 C. to 60 C. and that temperature maintained for about one hour at which time the conversion is complete.

The nitric acid which we prefer to use is water-white nitric acid with a specific gravity of 1.42. We have found that the yield is reduced when the nitric acid used has become darkened through exposure to suniieht. The nitration can be effected at a temperature Within the range of 0 C. to 56 C. and with from about four to one moles of concentrated nitric acid to The quaof the nitric acid used depends upon the tempera ture at which the nitration is carrie out. In general, the ratio of the nitric acid to iuran derivative is decreased as the nitration temperature is raised.

It is not essential that the temperature be held constant during nitration. However, wide fluctuations in the temperature should be avoided for there appears to be an optimum ratio of concentrated nitric acid to furan derivative for each temperature. We now prefer to conduct the nitration step at a temperature of id" CxiB" C. using slightly more than one mole of concentrated nitric acid for each mole of furan derivative.

Our nitration mixture is prepared by dissolving the concentrated nitric acid in acetic anhydride and then mixing the furan derivative slowly with that solution, or the furan derivative may be dissolved in a quantity of acetic anhydride and that solution may be added slowly to a solution of concentrated nitric acid in acetic anhydride. We now prefer to use a total of about 7.6 moles of acetic anhydride for each mole of furan derivative used. However, this ratio can be varied. We have found that an increase in the quantity of acetic anhydride used gives no appreciable difference in results but if only one-half that quantity of acetic anhydride should be used, the yield would be reduced.

The conversion of the nitration intermediate into the nitrofuran is preferably conducted by the addition of water and the base to a nitration mixture prepared through the use of concentrated nitric acid. The nitration intermediate formed through the use of fuming nitric acid can be converted directly into the nitrofuran by adding water and base to the nitration mixture, but in this case control of the reaction is very difiicult.

The nitration mixture is chilled, diluted with water, and brought to the desired pH value through the addition of a base The chilling can be accomplished by external means or by the addition of ice water The dilution ranges from one to three parts of Water to one part of nitration mixture, and can be accomplished by cold water or by a cold aqueous solution of the base. The base can be added in solution or separately. The quantity of the base added is suflicient to produce the desired pH value. The preferred pH value is 3.7 but may range from about 1.79 to about 4.66.

The conversion can be effected through the use of any base, organic or inorganic, which produces a buffer system in the presence of acetic acid. The use of an organic base, like pyridine, which is expensive and toxic, is not essential. An inorganic base such as trisodium phosphate, sodium hydroxide and potassium hydroxide is particularly well adapted for use in effecting the conversion. Of these, we prefer trisodium phosphate, for it gives a higher yield and a purer product than the others, and it is not necessary that the temperature of the nitration mixture be below 25 C. when it is added. When other bases are used, the temperature of the nitration mixture is reduced to between C. and 10 C. before the addition.

The rate of addition of the base to the nitration mixture is such that the temperature does not rise above 60 C. A conversion temperature of 55 C. is preferred. However, the conversion will take place at a temperature within the range of 25 C. to 60 C. and the mixture is held at such temperature, with stirring, for about one hour after the addition of the base, at which time the conversion is complete.

After the conversion has been completed, the nitrofuran can be removed from the mixture by filtration or by extraction with an immiscible solvent such as ether or benzene. It is then purifled by washing with cold water until free of acid and is recrystallized from alcohol or dried and distilled.

It is a special feature of our invention that it makes possible for the first time the production of 5-nitro-furfural diacetate on a commercial scale. That compound is used in the preparation of 5-nitro-2-furaldehyde semicarbazone which is a chemotherapeutic agent of outstand- 55 C. for one hour, the mixture cooled to 0 C ing value. However, our invention is not limited to the production of 5-nitrofurfural diacetate. It may be practiced to produce other nitrated furan derivatives.

In order that our invention will be clearly understood, we will describe specific examples of the preparation of 5-nitrofurfural diacetate and other nitrated furan derivatives in accordance with our invention:

EXAMPLE I 5-nitrofurjural diacetate A nitrating solution is prepared by adding 102 grams (1%; moles) of concentrated nitric acid U. S. P. (sp. gr. 1A2) dropwise, with stirring, to 720 cc. (7.6 moles) of acetic anhydride This addition takes about ten minutes and the temperature is kept below 40 C. by external cooling. Then, 96 grams (1 mole) of pure furfural is added to the nitrating solution so prepared, the temperature of the reaction being maintained at 40 0.:3" C. by the rate of addition. Stirring is continued for one-half hour after the addition has been completed to assure a complete reaction. During this time the reaction temperature remains at 40 0.13" C. without need for further control. Furfural diacetate is the equivalent of furfural in carrying out this reaction.

The temperature of the reaction mixture is then lowered to 10 C. and 600 cc. of cold water is added. The temperature rises to 20 C.-25 C. Enough of an approximately 20% w./w. aqueous trisodium phosphate solution (ca. 1200 cc.) to bring the pH of the solution to 3.7 is slowly added. The temperature is held below 60 C. during this addition. After all the phosphate solution has been added, the temperature of the reaction mixture is held at 55 C. for one hour. The mixture is then cooled to 20 C. and stirred for one hour at this temperature. The crystals are then filtered off, washed on the filter with one liter of cold water and dried at 50 C. Yield, 137 grams or 56%.

The product is recrystallized by warming to 71 C. with 800 cc. of ethyl alcohol (S. D. A. No. 1), filtering by suction and cooLng the filtrate to 20 C. The temperature is kept at 20 C. for one hour, the crystals are filtered ofi, washed on the,

filter with 50 cc. of cold alcohol and dried at 50 C. Yield, 121 grams. This is an overall yield of 50% of pure 5-nitrofurfural diacetate. M. P. 91-92 C.

EXAMPLE II 5-nitrofurjural diacetate 32 cc. (0.5 mole) of nitric acid is added dropwise, with stirring, to 132 cc. (1.4 moles) of acetic anhydride at such a rate that the temperature is maintained at 25 C. either by external cooling or by direct addition of small pieces of dry ice to the mixture. Then a solution of 24 g. (0.25 mole) of furfural in 4'7 cc. (0.5 mole) of acetic anhydride is added dropwise, with stirring, at 25 C. Stirring is continued for one-half hour after completion of the addition. Furfural diacetate is the equivalent of furfural in carrying out this reaction. 7

The reaction mixture is cooled to 0 C. in an ice bath and 2'71 g. of water is added. 30 g. of sodium hydroxide is then added at such a rate that the temperature of the solution does not rise above 55 C. to bring the pH of the solution to 3.7. The temperature is maintained at 50 C.-

and filtered. The product is washed on the filter with 250 cc. of cold water and dried at 50 C. Yield, 29 grams or 48%.

EXAMPLE III 5-nitrofurfuryl propz'onate 51 grams mole) of nitric acid (sp. gr. 1.42) is added dropwise, with stirring, to 360 cc. of acetic anhydride, the temperature of the reaction being held below 40 C. by external cooling. Then '77 grams mole) of furfuryl propionate is added dropwise with stirring at such a rate that the temperature can be readily kept, with external cooling, at 46 Ci3 C. Stirring is continued at 40 C. for hour after all the propionate has been added.

The reaction mixture is cooled to C. and 300 grams of water added. Then 250 cc. of a 20% (by weight) solution of sodium hydroxide is added at such a rate that the reaction temperature does not exceed 55 C. The temperature is maintained, with stirring, at 50 C.-55 C. for one hour. The mixture is cooled to 0 C. and held, with stirring, for one hour. The solid is then filtered off, washed with water and dried. Yield, 49 grams or 49%.

EXAMPLE IV 5-nitro-methyl furoate The procedure is the same as that described under Example III, substituting 63 grams /2 mole) of methyl furoate for the furfuryl propionate. Yield, 45 grams or 53%.

What is claimed is:

1. The process of nitrating a furan derivative to produce a 5-nitrofuran, which comprises the step of forming a nitration intermediate by adding the furan derivative to acetic anhydride and concentrated nitric acid, and maintaining the temperature of the ingredients between 0 C. and 50 C. during the addition and until completion of the reaction; and the step of converting the nitration intermediate into the nitrated furan derivative, which comprises diluting the nitration mixture with from about one to three volumes of water and adding a base which forms a bufier system in the presence of acetic acid until a pH value within the range of 1.79 and 4.66 is produced, and maintaining the temperature of the mixture between 25 C. and 60 C. during said addition and until the conversion is complete.

2. The process of nitrating a furan derivative to produce a 5-nitrofuran, which comprises the step of forming a nitration intermediate by adding one part of the iuran derivative to at least four parts of acetic anhydride and from one to four parts of concentrated nitric acid, and maintaining the temperature of the ingredients between 0 C. and 50 C. during the addition and until completion of the reaction; and the step of converting the nitration intermediate into the nitrated furan derivative, which comprises diluting the nitration mixture with from one to three volumes of water and adding a base which forms a buffer system in the presence of acetic acid until a pH value within the range of 1.79 to 4.66 is produced, and maintaining the temperature of the mixture between 25 C. and 60 C. during said addition and. until the conversion is complete.

3. The process of nitrating a furan derivative to produce a 5-nitrofuran, which comprises the step of forming a nitration intermediate by adding one part of the furan derivative to at least four parts of acetic anhydride and from one to two parts of concentrated nitric acid, and maintaining the temperature between 25 C. and C. during the addition and until the completion of the reaction; and the step of converting the nitration intermediate into the nitrated furan derivative, which comprises diluting the nitration mixture with from one to three volumes of water and adding a base Which forms a buffer system in the presence of acetic acid until a pH value within the range of 1.79 and 4.66 is produced, and maintaining the temperature of the mixture between 25 C. and 60 C. during said addition and until the conversion is complete.

4. The process of nitrating a furan derivative to produce a 5-nitrofuran, which comprises the step of forming a nitration intermediate by add.- ing one part of the furan derivative to at least four parts of acetic anhydride and from one to two parts of concentrated nitric acid, and maintaining the temperature between 25 C. and 45 C. during the addition and until the completion of the reaction; and the step of converting the nitration intermediate into the nitrated furan, derivative, which comprises diluting the nitration mixture with from one to three volumes of ice water and adding an inorganic base until a. pH value within the range of 1.79 to 4.66 is produced, and maintaining the temperature of the mixture between 25 C. and 60 C. during said. addition and until the conversion is complete.

5. The process of nitrating a furan derivative to produce a 5-nitrofuran, which comprises the step of forming a nitration intermediate by adding the furan derivative to acetic anhydride and concentrated nitric acid, and maintaining the temperature of the ingredients between 6 C. and C. during the addition and until completion of the reaction; and the step of converting the nitration intermediate into the nitrated furan derivative, which comprises diluting the nitration mixture with from one to three volumes of water and adding a base which forms a buffer system in the presence of acetic acid until a pH value of about 3.7 is produced, and maintaining the temperature of the mixture at about C. during said addition and until the conversion is complete.

6. The process of nitrating a furan derivative. to produce a 5-nitrofuran, which comprises the step of forming a nitration intermediate by adding about one part of the furan derivative to about 7.6 parts of acetic anhydride and from one to two parts of concentrated nitric acid, and

maintaining the temperature of the ingredients between 25 C. and 45 C. during the addition and until completion of the reaction; and the step of converting the nitration intermediate into the nitrated furan derivative, which comprises diluting the nitration mixture with about two volumes of ice water and adding an inorganic base until a pH value of about 3.7 is produced, and maintaining the temperature of the mixture at about 55 C. during said addition and until the conversion is complete.

7. The process of nitrating furfural to produce 5-nitrofurfural diacetate, which comprises the step of forming a nitration intermediate by adding the furfural to acetic anhydride and concentrated nitric acid, and maintaining the temperature of the ingredients between (3 C. and 50 C. during the addition and until completion of the reaction; and the step of converting said intermediate into 5-nitrofurfural diacetate, which comprises diluting the nitration mixture with from one to three volumes of water and adding a base which vforms a buffer system in the presence of acetic acid until a pH value within the range of 1.79 to 4.66 is produced, and maintaining the temperature of the mixture between 25 C. and 60 C. during said addition and until the conversion is complete.

8. The process of nitrating furfural to produce 5-nitroiurfural diacetate, which comprises the step of adding about one part of furfural to about 7.6 parts of acetic anhydride, and between one and two parts of nitric acid having a specific gravity of about 1.40, and maintaining the temperature of the ingredients between 25 C. and 45 C. during the addition and until completion of the reaction; and the step of converting the -nitration intermediate into the nitrated furan derivative, which comprises diluting the nitration mixture with from one to three volumes of ice water and adding trisodium phosphate until a pH value of about 3.7 is produced, and maintaining the temperature of the mixture at about 55 C. during said addition and until the conversion is complete.

19. The method of nitrating furfuryl propionate to produce 5-nitrofurfuryl propionate, which comprises adding about one part of furfuryl propionate to about 7.6 parts of acetic anhydride and between one and two parts of concentrated nitric acid, and maintaining the temperature of the ingredients between 25 C. and 40 C. during the addition and until completion of the reaction; and the step of converting the nitration intermediate into 5-nitrofurfuryl propionate, which comprises diluting the nitration mixture with from one to three volumes of water and adding sodium hydroxide until a pH value of about 3.7 is produced, and maintaining the temperature of the mixture at about 55 C. during said addition and until the conversion is complete.

10. The process of nitrating methyl furoate to produce 5-nitro-methyl furoate, which comprises the step of forming a nitration intermediate by adding about one part of methyl furoate to about 7 .6 parts of acetic anhydride and from one to two parts of concentrated nitric acid, and maintaining the temperature of the ingredients between 25 C. and 45 C. during said addition and until completion of the reaction; and the step of converting the nitration intermediate into 5-nitromethyl furo-ate, which comprises diluting the nitration mixture with from one to three volumes of water and adding sodium hydroxide until a pH value of about 3.7 is produced, and maintaining the temperature of the mixture at about 55 C. during said addition and until the conversion is complete.

. 11. In the process of nitrating a furan derivative to produce a 5-nitro-furan, the step of forming a nitration intermediate, which comprises adding the furan derivative to acetic anhydride and concentrated nitric acid, and maintaining the temperature of the ingredients between C. and 50 C. during the addition and until completion of the reaction.

, 12. In the process of nitrating a furan derivative to produce a -nitrofuran, the step of forming a nitration intermediate, which comprises adding about one part of the furan derivative to from four to eight parts of acetic anhydride and from one to two parts of concentrated nitric acid, and maintaining the temperature of the ingredients between 25 C. and 45 C. during the addition and until completion of the reaction.

" 13. In the process of nitrating furfural to produce 5-nitrofurfural diacetate, the step of forming a nitration intermediate, which comprises adding about one part of furfural to at least four parts of acetic anhydride and from one to two parts of concentrated nitric acid, and maintaining the temperature of the ingredients between 25 C. and 45 C. during the addition and until completion of the reaction.

14. In the process of nitrating a furan derivative to produce a e-nitroiuran, the step of converting into a nitrofuran a nitration intermediate formed by the reaction of the furan derivative, acetic anhydride and nitric acid, which comprises diluting the nitration mixture with from about one to three volumes of water and adding a base which forms a bufier system in the presence of acetic acid until a pH value within the range of about 1.79 to about 4.66 is produced, and maintaining the temperature of the mixture between 25 C. and 60 C. during said addition and until the conversion is complete.

15. In the process of nitrating a furan deriva tive to produce a 5-nitrofuran, the step of converting into a nitrofuran a nitration intermediate formed by the reaction of the furan derivative, acetic anhydride and nitric acid, which comprises diiuting the nitration mixture with from one to three volumes of ice water and adding inorganic base until a pH value within the range of about 1.79 to about 4.66 is produced, and maintaining the temperature of the mixture between ?5" C. and 60 C. during said addition and until the conversion is complete.

16. In the process of nitrating a furan derivative to produce a 5-nitrofuran, the step of converting into a nitrofuran a nitration intermediate formed by the reaction of the furan derivative, acetic anhydride and nitric acid, which coinprises diluting the nitration mixture with from one to three volumes of ice water and adding a base which forms a buifer system in the presence of acetic acid until a pH value or about 3.7 is produced, and maintaining the temperature of the mixture at about 55 C. during said addition and until the conversion is complete.

17. In the process or" nitrating furfural .to produce 5-nitrofurfural diacetate, the step of converting into fi-nitrofurfural diacetate a nitration intermediate formed by the reaction of furfural, acetic anhydride and concentrated nitric acid, which comprises diluting the nitration mixture with from one to three volumes of ice water and adding trisodium phosphate until a pH value of about 3.7 is produced, and maintaining the temperature of the mixture at about 55 C. during said addition and until the conversion is complete.

WALTER KIMEL. JOHN H. COLEMAN. WILLIAM B. S'TILLMAN.

REFERENCES CITED The following references are of record in the file of this patent:

Gilman, Jr. of American Chem. Soc., vol. 52, pages 2550 to 2552.

Rinkes, Recueil Des Travaux Chimiques Des Pays, BAS Tome 49, 1930, pages 1118-1121.

Usanovich et al., Chem. Abstracts, vol. 39, page 4540. 

